Trazodone is a serotonin-2 receptor antagonist/reuptake inhibitor that also decreases extracellular gamma-amino-butyric acid (GABA) levels in the cerebral cortex, through the blockade of 5-hydroxytryptamine2A (5-HT2A) receptors. This decrease is accompanied by an increase in (5-HT) release. Higher doses of trazodone inhibit 5-HT transport and this uptake inhibition results in a further increase in 5-HT levels. It is contemplated that this double mechanism may be responsible for the anti-depressant properties of trazodone. Moreover, the interaction between the GABAergic and serotoninergic systems may explain its sedative, anxiolytic properties.
Trazodone is therefore a psychoactive compound with sedative and anti-depressant properties. It is rapidly absorbed from the upper gastro-intestinal tract and is extensively metabolized after oral administration. It is normally used to relieve symptoms of depression such as feelings of sadness, worthlessness, or guilt; loss of interest in daily activities; changes in appetite; tiredness; thoughts of death or suicide; and insomnia. Trazodone may also be used for other purposes, and details thereof are well documented in the art.
Trazodone is a triazolopyridine derivative of the formula
which is shown in its normally used hydrochloride form. Preparation of this compound was first disclosed in U.S. Pat. No. 3,381,009 which issued in 1968 to G. Palazzo et al.
The solubility of trazodone is pH dependent and has a pKa of 6.74 in water. As a result, trazodone is highly soluble in acid media (as found in the stomach and upper intestines) i.e., when below its pKa. In contrast, when above its pKa, its solubility is very low, for example, in the neutral and basic conditions of the lower intestine. Such insolubility obviously has an effect on its dissolution and, therefore, on the availability of the drug for absorption in the lower intestine. These features would be expected to hinder the development of long acting (for example, greater than 8 hours) forms of trazodone, which require substantially uniform absorption along the length of the gastrointestinal tract, in particular, absorption during passage through both the upper and lower intestinal tracts.
As with many drugs, trazodone is normally prescribed as an immediate release form for use two times (BID) or three times (TID) a day, with all the inconveniences and disadvantages that this involves. For example, BID or TID dosing with immediate release forms of trazodone results in concentrations of the drug in the blood that do not remain within the so-called therapeutic window and which, therefore, can be associated with higher risks of dose related adverse effects when reaching high levels, or lower degree of efficacy when reaching low levels. In addition, multiple daily doses may lead to several periods of drowsiness throughout the day associated with peak trazodone concentrations occurring immediately after administration.
As a result, there is a need for a once a day (OAD) formulation of trazodone that from a single tablet rapidly achieves and maintains stable, effective concentrations over 24 hours and more and that is pH-independent in its release profile so that trazodone may be uniformly absorbed along substantially the entirety of the upper and lower gastrointestinal tract, thereby reducing the frequency and severity of side effects such as drowsiness during the day.